title: Inositol 1,4,5-trisphosphate (IP3) receptor up-regulation in hypertension is associated with sensitization of Ca2+ release and vascular smooth muscle contractility.
abstract: Resistance arteries show accentuated responsiveness to vasoconstrictor agonists in hypertension, and this abnormality relies partly on enhanced Ca(2+) signaling in vascular smooth muscle (VSM). Although inositol 1,4,5-triphosphate receptors (IP3Rs) are abundant in VSM, their role in the molecular remodeling of the Ca(2+) signaling machinery during hypertension has not been addressed. Therefore, we compared IP3R expression and function between mesenteric arteries of normotensive and hypertensive animals. Levels of IP3R transcript and protein were significantly increased in mesenteric arteries of hypertensive animals, and pharmacological inhibition of the IP3R revealed a higher contribution of IP3-dependent Ca(2+) release to vascular contraction in these arteries. Subsequently, we established cultured aortic VSM A7r5 cells as a cellular model that replicates IP3R up-regulation during hypertension by depolarizing the VSM cell membrane. IP3R up-regulation requires Ca(2+) influx through L-type Ca(2+) channels, followed by activation of the calcineurin-NFAT axis, resulting in IP3R transcription. Functionally, IP3R up-regulation in VSM is associated with enhancement and sensitization of IP3-dependent Ca(2+) release, resulting in increased VSM contraction in response to agonist stimulation.
authors.affiliation: From the Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Qatar Foundation, Education City, Doha 24144, Qatar.
authors.forename: Haissam
authors.initials: H
authors.lastname: Abou-Saleh
authors.forename: Asif R
authors.initials: AR
authors.lastname: Pathan
authors.forename: Arwa
authors.initials: A
authors.lastname: Daalis
authors.forename: Satanay
authors.initials: S
authors.lastname: Hubrack
authors.forename: Hamda
authors.initials: H
authors.lastname: Abou-Jassoum
authors.forename: Hamda
authors.initials: H
authors.lastname: Al-Naeimi
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Rusch
authors.forename: Khaled
authors.initials: K
authors.lastname: Machaca
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D002460:Cell Line; D006973:Hypertension / Q000378:metabolism* / Q000473:pathology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000096:biosynthesis*; D008564:Membrane Potentials; D008638:Mesenteric Arteries / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009119:Muscle Contraction; D009124:Muscle Proteins / Q000096:biosynthesis*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D020746:Calcium Channels, L-Type; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; D019703:Calcineurin; D002118:Calcium
keywords: A7r5; Calcineurin; Calcium Signaling; Hypertension; IP3 Receptor; NFAT Transcription Factor; Vascular Smooth Muscle Cells